Vitamin-D- PRODH- & DTNBP1-Induced Hyperprolinemia:Schizophrenia Risk & Treatment

维生素-D-PRODH-

• 批准号: 8775262
• 负责人: CATHERINE L CLELLAND
• 金额: $ 43.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775262
• 关键词: 22q11; 22q11.2; 22q11.21; Adult; Amino Acids; Amphetamines; Animals; Astrocytes; Attenuated; Behavioral; Biological; Biological Assay; Biological Models; Blood; Brain; Catabolism; Chromosomes; Cognitive; Cognitive deficits; Cohort Studies; Data; Development; Diet; Dopamine; Enzymes; Exhibits; Fasting; Figs - dietary; Gene Expression; Gene Mutation; Genes; Genetic Risk; Genetic Variation; Genomics; Glutamates; Health; Hippocampus (Brain); Human; Hypersensitivity; Impaired cognition; Impairment; Influentials; Intervention; Lead; Learning; Link; Measures; Mediating; Memory impairment; Modeling; Molecular; Molecular Abnormality; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neonatal; Neuromodulator; Neurons; Neurotransmitters; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Primary Cell Cultures; Proline; Proline Dehydrogenase; Public Health; Relative (related person); Reporting; Risk; Risk Factors; Sampling; Schizophrenia; Short-Term Memory; Signal Transduction; Source; Study Section; Supplementation; Symptoms; Synapses; Testing; Thiazolidinediones; Tissues; Toxic effect; Up-Regulation; Variant; Vitamin D; Vitamin D2; Work; cognitive performance; cohort; design; early childhood; endophenotype; functional restoration; gamma-Aminobutyric Acid; genetic variant; in vivo; in vivo Model; microdeletion; mouse model; null mutation; prepulse inhibition; prevent; response; restoration; rosiglitazone; screening

DESCRIPTION (provided by applicant): The highest known genetic risk of schizophrenia (SZ) is conferred by hemizygous microdeletion of chromosome 22q11. The proline dehydrogenase gene (PRODH) is located in the common deleted region, and encodes the enzyme that catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and the peripheral hyperprolinemia arising from PRODH mutations or CNVs encompassing PRODH, has been associated with cognitive impairment and decreased IQ. We recently reported a highly significant association of hyperprolinemia with SZ. We now provide evidence that two further independent SZ risk factors: Low vitamin-D status, and mutation of the dysbindin gene (Dtnbp1), also cause hyperprolinemia. Our findings suggest convergence of the biological pathways regulated by vitamin-D and DTNBP1, via loss of PRODH expression, with elevated proline as a common SZ endophenotype. Studies have documented the dysfunctional consequences of hyperprolinemia, such as aberrant glutamatergic and dopamine signaling leading to, for example, cognitive deficits and attenuated prepulse inhibition (PPI). Targeting hyperprolinemia in the Dtnbp1 model may therefore positively impact neurotransmitter signaling and restore function. This proposed study is designed to test our hypotheses under the following Specific Aims. Aim 1: To test the relative molecular contributions of low Vitamin D, and PRODH, and DTNBP1 gene variants, to SZ- associated hyperprolinemia. In a SZ patient and control sample (n=250), we will measure plasma proline and Vitamin-D levels, confirming the strong relationship between elevated proline and low Vitamin-D. From our preliminary data, we anticipate that 80% of the measured hyperprolinemia will arise from low vitamin-D, while DTNBP1 and PRODH variants will be responsible for the remaining 20%. Thus, we will perform molecular analyses on our complete study cohort (404 subjects), screening for PRODH, and DTNBP1 variants that alter gene expression, and testing for variant associations, plus interactions with low Vitamin-D, on the outcome of proline elevation. Aim 2: To examine the molecular pathway leading to hyperprolinemia in the Dtnbp1 model. Aim 2A. Molecular analyses will include assay of peripheral and CNS tissue expression of Prodh, p53 regulated genes, and Comt (downstream of Prodh), as well as of cortical, hippocampal and peripheral proline levels. Aim 2B. Utilizing primary neurons and astrocytes from sdy-/- and Prodh+/- mice, we will directly upregulate Prodh expression, via treatment with Vitamin D and the thiazolidinedione drug Rosiglitazone (RZG), testing for restoration of Prodh expression and decreased cellular proline. Aim 3: To target hyperprolinemia in the Dtnbp1 model in vivo. We will examine whether treatment with Vitamin D (Aim 3a), RZG (Aim 3b), and, to seek to reduce the impact of off-target effects, a proline-deficient diet (Aim 3c), compared to vehicle- treatment alone, restores the above pathway in vivo, and prevents or alleviates the Sdy-/- deficit in, for example, PPI and spatial working memory.

描述（由申请人提供）：精神分裂症（SZ）的最高已知遗传风险由染色体22 q11的半合子微缺失引起。脯氨酸脱氢酶基因（PRODH）位于共同缺失区，编码催化脯氨酸催化的酶。脯氨酸是神经元突触的神经调质，由PRODH突变或包含PRODH的CNV引起的外周高脯氨酸血症与认知障碍和智商降低相关。我们最近报道了高脯氨酸血症与SZ的高度显著相关性。我们现在提供的证据表明，另外两个独立的SZ风险因素：低维生素D状态和dysbindin基因（Dtnbp 1）突变，也会导致高脯氨酸血症。我们的研究结果表明，维生素D和DTNBP 1调节的生物途径的收敛，通过PRODH表达的损失，与升高的脯氨酸作为一个共同的SZ内表型。研究已经记录了高脯氨酸血症的功能障碍后果，例如异常的多巴胺能和多巴胺信号传导，导致例如认知缺陷和减弱的前脉冲抑制（PPI）。因此，在Dtnbp 1模型中靶向高脯氨酸血症可能会积极影响神经递质信号传导并恢复功能。这项拟议的研究旨在根据以下具体目标测试我们的假设。目的1：检测低维生素D、PRODH和DTNBP 1基因变异体对SZ相关高脯氨酸血症的相对分子贡献。在SZ患者和对照样品（n=250）中，我们将测量血浆脯氨酸和维生素D水平，证实脯氨酸升高和维生素D降低之间的强相关性。根据我们的初步数据，我们预计80%的高脯氨酸血症将由低维生素D引起，而DTNBP 1和PRODH变体将负责剩余的20%。因此，我们将对我们的完整研究队列（404名受试者）进行分子分析，筛选PRODH和DTNBP 1变异体，改变基因表达，并测试变异体相关性，加上与低维生素D的相互作用，对脯氨酸升高的结果。目的2：在Dtnbp 1模型中研究导致高脯氨酸血症的分子途径。目标2A。分子分析将包括外周和CNS组织表达的p53调节基因，和Comt（p53调节基因的下游），以及皮质，海马和外周脯氨酸水平的测定。目标2B利用来自sdy-/-和BTH +/-小鼠的原代神经元和星形胶质细胞，我们将通过用维生素D和噻唑烷二酮药物罗格列酮（RZG）处理来直接上调BTH表达，测试BTH表达的恢复和细胞脯氨酸的减少。目的3：在体内Dtnbp 1模型中靶向高脯氨酸血症。我们将检查与单独的媒介物处理相比，用维生素D（Aim 3a）、RZG（Aim 3b）和脯氨酸缺乏饮食（Aim 3c）处理以寻求减少脱靶效应的影响，是否在体内恢复上述途径，并预防或减轻例如PPI和空间工作记忆中的Sdy-/-缺陷。